title: The effects of a newly developed nonsteroidal anti-inflammatory drug (M-5011) on arachidonic acid metabolism in rheumatoid synovial fibroblasts.
abstract: M-5011 (d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid) is a newly developed nonsteroidal anti-inflammatory drug (NSAID) that displays potent anti-inflammatory and analgesic properties with low ulcerogenic activities in animal models. In this study, the effects of M-5011 on arachidonic acid (AA) metabolism in synovial fibroblasts from patients with rheumatoid arthritis were evaluated and compared with those of other NSAIDs in vitro. Either M-5011 or ketoprofen potently inhibited prostaglandin (PG) E2 production by cyclooxygenase (COX)-2 from exogenous AA in interleukin-1beta (IL-1beta)-stimulated cells. The IC50 values of M-5011 and ketoprofen were 4.4 x 10(-7) and 5.9 x 10(-7) M, respectively. However, diclofenac and indomethacin were one order less potent. Although the latter two drugs exhibited time-dependent and irreversible inhibition on COX-2 in IL-1beta-stimulated cells, the inhibitory effects of M-5011 and ketoprofen were reversible. PGE2 production by COX-1 from exogenous AA in non-stimulated cells was also inhibited by M-5011 with a potency less than that of ketoprofen. In addition, M-5011 inhibited [14C]AA release from prelabeled synovial cells stimulated with bradykinin. However, ketoprofen hardly affected the [14C]AA release. It is likely that the effects of M-5011 on AA metabolism are, in part, responsible for its in vivo efficacy and safety profile.
authors.affiliation: Research & Development Laboratories, Maruho Co., Ltd., Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Tobetto
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: M
authors.initials: M
authors.lastname: Kataoka
authors.forename: T
authors.initials: T
authors.lastname: Ando
authors.forename: K
authors.initials: K
authors.lastname: Sugimoto
authors.forename: M
authors.initials: M
authors.lastname: Himeno
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism*; D001920:Bradykinin; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D007660:Ketoprofen / Q000494:pharmacology; D008565:Membrane Proteins; D008875:Middle Aged; D010666:Phenylpropionates / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002250:Carbon Radioisotopes; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D010666:Phenylpropionates; D016718:Arachidonic Acid; C104139:2-(4-(3-methyl-2-thienyl)phenyl)propionic acid; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D001920:Bradykinin; D007213:Indomethacin